DEFINITION

• A case or a family with hormone-secreting or hormone- producing neoplasia in multiple tissue types

• It encompasses several types of etiology, varying from two coincidental tumors to complex patterns of tumor types. Certain patterns of tumor types recur reproducibly among unrelated cases or among unrelated families

MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES

SIX MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES AND THEIR MAIN CHARACTERISTICS

Endocrine Tumors Expressed in Multiple Endocrine Neoplasia Types 1 and 2

MEN1-Related Endocrine Tumors And Their Prevalence

Parathyroid Adenomas (90%)

GEP Gastrinoma (40%)

Insulinoma (10%)

Others (VIPoma, PPoma, SSoma, Glucagonoma) (2%)

Non-functioning (20%)

Anterior Pituitary Functioning: PRLoma (20%)

GH-, GH/PRL-, TSH-, ACTH-secreting, or Non-functioning (17%)

Foregut Carcinoids Thymic (2%)

Bronchial (2%)

Gastric (ECLoma) (10%)

Adrenal Gland Non-functioning (20%)

MEN1-Related Non-Endocrine Tumors And Their Prevalence

 

Cutaneous Tumors Lipomas (30%)

Facial angiofibromas (85%)

Collagenomas (70%)

 

Central Nervous System Meningiomas (5%)

Ependymomas (1%)

 

Others Leyomiomas (10%)

Familial Hypocalciuric Hypercalcemia (FHH)/Neonatal Severe Hyperparathyroidism (NSHPT)/Neonatal Hyperparathyroidism (NHPT)/Autosomal Dominant Moderate Hyperparathyroidism (ADMH)

Hyperparathyroidism- Jaw Tumors (HPT-JT) Familial Isolated Primary Hyperparathyroidism (FIHPT)

Multiple Endocrine Neoplasia Type 2A (MEN2A)

Multiple Endocrine Neoplasia Type 1 (MEN1)

Clinical syndromes of familial primary hyperparathyroidism

MOLECULAR DIAGNOSIS CAN NOW BE INCORPORATED INTO THE MANAGEMENT OF PATIENTS WITH THESE AUTOSOMAL

DOMINANT SYNDROMES

however

VALUE OF GENETIC INFORMATION IN THE CONTEXT OF CLINICAL

SCREENING AND EARLY SURGERY VARIES AMONG THESE DISORDERS

InactivatingHRPT2/oncusuppressor1q25-q31HPT-JT/607393

InactivatingCaSR3q13.3-q21FHH-NSHPT/NHPT 145980-239200

Atypical inactivating CaSR3q13.3-q21ADMH/601199

Inactivating for MEN1, HRPT2, and CaSR

genes

MEN1/oncosuppressor, HRPT2/oncosuppressor,

CaSRand still unknown genes

11q13, 1q25-q31, 3q13.3-q21/2p13.3-14, and still unknown loci

FIHPT/145000

ActivatingRET/proto-oncogene10q11.1MEN2A/171400

InactivatingMEN1/oncosuppressor11q13MEN1/131100

Type of germline mutation

Gene/activityChromosomal localization

Syndrome/OMIM#°

Chromosomal localization and genetic defects underlying each familial form of hereditary hyperparathyroidism

Gene Mutation (%)

90

98

10-18

100

N.R.

60

ONE DECADE FOLLOWING THE CLONING OF THE MEN1 GENE 1336 mutations and 24 polymorphisms

MUTATIONS (in 1091 families) POLYMORPHISMS

Adapted from: JCEM 92:3389, 2007; Hum Mutat 29:22, 2008

• >70% lead to truncated forms of menin• 4% are large deletions• Four occur frequently• No genotype/phenotype correlations

Therefore the screening becomes time consuming, arduous and expensive

• 12 in the coding regions• 9 in the introns• 3 in untranslated regions

Useful for segregation analysis if MEN1 mutation is not found

CHARACTERISTICS OF THE MUTATED MEN1 CASES

• Sporadic cases: 6-10% had MEN1 mutations

Familial cases: 90-94% had MEN1 mutations

• A mutation is most likely when one typical endocrine tumor and at least one of the following is present:

1. A first degree relative with a major endocrine tumor2. Age of onset less than 30 yr3. Multiple pancreatic tumors4. Parathyroid hyperplasia

Adapted from: JCEM 92:3389, 2007; Exp Clin Endocrinol Diabetes 115:509, 2007; Hum Mutat 29:22, 2008

CAN GENE TESTING DECREASE THE MORBIDITY AND MORTALITY ASSOCIATED WITH MEN1?

• Asymptomatic gene carriers will NOT be treated with prophylactic or early surgery• Familial screening:

1. In children by the first decade

2. Asymptomatic gene carriers are closely followed

3. A negative test precludes from periodic screening

The identification of MEN1 mutations is of help in clinical management of patients and their families

and in life-planning decisions of affected patients

J Clin Endocrinol Metab, September 2012, 97(9):2990–3011

Basis for a diagnosis of MEN1 in individuals

Adapted from: JCEM 97:2990, 2012

Suggested biochemical and radiological screening in individuals at high risk of developing MEN1

Adapted from: JCEM 97:2990, 2012

An approach to screening in MEN1

Adapted from: JCEM 97:2990, 2012

MEN syndromes and their characteristic tumors and associated genetic abnormalities

Adapted from: JCEM 97:2990, 2012

SCHEMATIC REPRESENTATION OF THE RET TYROSINE KINASE RECEPTOR

ALL THE MEN2 VARIANTS ARE CAUSED BY RET GERMLINE MUTATION

Stratification risk according to RET mutation

•codons 883, 918, 922 (exons 15, 16) MEN2Bhighest risk for aggressive MTC; operated on within the first 6 months

•codons 611, 618, 620, 634 (exons 10, 11) MEN2A/FMTCintermediate risk; thyroidectomy performed before the age of 5 yr.

•codons 609, 768, 790, 791 804, 891 (exons 10, 13, 14, 15) MEN2A/FMTC lower risk; operated on at a later stage

American Thyroid Association risk level and timing of prophylactic thyroidectomy in MEN2A*

Adapted from: Surgery 148:1302, 2010

Recommendations for screening procedures and time of prophylactic thyroidectomy.*

Adapted from: Best Practice and Research Clinical Endocrinology and Metabolism 24:371, 2010

Graphic representation of the nuclear interactions of p27

Adapted from: Neuroendocrinology  2010

Clinical and molecular characteristics of the identified CDKN1B/p27 variants

Adapted from: Neuroendocrinology  2010

Organizzazione del Centro di Riferimento T.E.E. della Regione Toscana nell’Ambito

dell’A.O.U.C.

Rapporti costanti con i pazienti ed i familiari per follow-up e risposta dei

test geneticiSOD Patologia Chirurgica

Reparto di Degenza SOD Medicina Interna 2

Front line Ambulatorio

Day Hospital

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